Intra-fractional organ motion is a predominant limiting factor for the maximum exploitation of modern prostate intensity modulated radiation therapy (IMRT) or volumetric modulated radiation therapy (VMAT). Adverse influence of the organ motion is further aggravated in hypofractionated treatment because of protracted dose delivery. In this project we will develop a real-time fiducial tracking strategy using a combined MV and kV imaging to solve the problem of intra-fraction prostate movement. The underlying hypothesis of this work is that real-time image guided prostate radiation therapy will greatly reduce the uncertainty in beam targeting and provide substantially improved dose distributions required to achieve greater local tumor control while reducing the probability of normal tissue complications. Specific aims of the project are to (1) Refine a hybrid MV/kV image acquisition protocol for IMRT and VMAT;(2) Evaluate the potential clinical impact of the hybrid image guidance technique through a pilot clinical study. Successful completion of this investigation will provide radiation oncology discipline a critically needed means to treat prostate cancer, and afford a powerful way for us to safely and reliably escalate the radiation dose using IMRT/VMAT. Given its significant promise to optimally cater for intra-fractional uncertainties, successful completion of the project should lead to substantial improvement in prostate cancer patient care. PUBLIC HEALTH RELEVANCE: In current prostate intensity modulated radiation therapy (IMRT) or volumetric modulated radiation therapy (VMAT), the adverse effect of intra-fractional prostate motion is compensated by introducing a large PTV margin, which leads to irradiation of adjacent critical organs and limits the prostate dose escalation. With the goal of rapidly deploying a previously developed kV/MV real-time tumor tracking technique into routine clinical practice, in this R21 application we plan to conduct a series of evaluations of the efficacy and clinical potential of the real-time image guidance strategy for prostate radiation therapy. Successful completion of this investigation will provide a critically needed means for treating prostate cancer and afford a powerful way for us to safely and reliably escalate radiation dose using IMRT.